I. Field of the Invention
The present invention relates to methods of treating disorders having an aberrant immune response component, including cancers and autoimmune disorders. These methods relate in particular to inhibiting or stimulating the immunomodulatory function of ERp5 located on the surface of tumor cells, activated T-cells, dendritic cells, and other cell types.
II. Background
Receptors that inhibit or activate natural killer (NK) cells can be expressed on T cells where they modulate T cell antigen receptor (TCR)-CD3 complex-dependent responses. Among these receptors is NKG2D, which interacts with ligands that are absent from most normal cells but can be transcriptionally induced by generic mechanisms of chromatin remodeling and cellular stress. In humans, NKG2D ligands include the major histocompatibility complex class I-related chain A polypeptide (MICA), which is frequently associated with epithelial tumors, induced by microbial infections, and aberrantly expressed in certain autoimmune disease lesions. Upon ligand engagement, NKG2D conveys directly activating or costimulatory signals via the paired DAP10 adaptor protein. NKG2D may thus promote cancer and infectious disease immunity but worsen autoimmune disease progression.
Consistent with its role in effector responses, NKG2D is present on virtually all NK cells and CD8 T cells but absent on most CD4 T cells. One exception to this rule is seen in rheumatoid arthritis (RA), where the severity of autoimmune and inflammatory joint disease correlates with large numbers of autoreactive CD4 T cells with NKG2D expression that is cytokine (IL-15 and TNF-α) induced (induced NKG2D+CD4+ T cells). These T cells are cytotoxic, produce inflammatory cytokines, and are stimulated by RA synoviocytes which have aberrant expression of the NKG2D ligand MICA. Thus, NKG2D binding to synoviocyte MICA may promote the self-perpetuating pathology in RA and presumably certain other autoimmune diseases as well (Groh et al., 2003).
Large expansions of NKG2D+CD4+ T cells have also been reported in cancer patients with tumors that express membrane-bound MIC and shed soluble MICA and presumably MICB. As with the NKG2D+CD4+ T cells in RA, these T cells are autoreactive; however, their expression of NKG2D is constitutive and not cytokine induced and they are non-cytotoxic (constitutive NKG2D+CD4+ T cells). Moreover, the NKG2D+CD4+ T cells in cancer patients have suppressor functions and thus resemble regulatory T cells. They produce IL-10 and TGFβ, and secrete Fas ligand (FasL), causing growth arrest of other T cells that lack NKG2D signaling, which protects from Fas/FasL-mediated cell cycle arrest (Groh et al., 2006). The increased frequencies of the NKG2D+CD4+ T cells in cancer patients result from proliferative expansions that are driven by NKG2D costimulation upon binding of membrane-associated or soluble MIC ligands. Thus, shedding of the soluble MIC ligands of NKG2D negatively imprints on immune responses, thus enabling tumor immune evasion. Moreover, soluble MICA induces downmodulation and degradation of NKG2D on NK cells and CD8 T cells, thus diminishing anti-tumor effector responses (Groh et al., 2001).
Central to this application is the mechanism of shedding, which is enabled by endoplasmic reticulum protein 5 (ERp5), a disulphide isomerase family member. ERp5 and MIC form mixed disulphide complexes on the surface of tumor cells, from which soluble MICA (and MICB) is released after proteolytic cleavage near the cell membrane. This mechanism involves reduction of the disulphide bond in the membrane-proximal α3 of MIC proteins, which presumably imposes a large conformational change that enables cleavage. By enabling the shedding of MIC proteins, ERp5 thus promotes expansions of ‘immunosuppressive’ type NKG2D+CD4+ T cells (constitutive NKG2D+CD4+ T cells), as well as impairment of NK cell and CD8 T cell functions via NKG2D downmodulation and degradation, in cancer patients.
Pertinent to this application, ERp5 is also present on activated T cells and monocyte-derived dendritic cells (DC). Binding of soluble MIC proteins to ERp5 induces a signaling event, presumably through an associated effector protein, which results in altered cytokine production by T cells and DC, and impairs maturation of DC.